As demonstrated in this review, during the last two decades a considerable number of compounds have been investigated as substitutes for phthalimide or its potassium salt in the Mitsunobu and Gabriel reactions. Their major advantages are 2-fold: Much milder and rather specific conditions can be used for the final deprotection than are required for phthaloyl, and alkylation can, if required, be carried out twice, in which case also secondary amines are obtained. Several of the novel reagents are easily made, and they can be alkylated in the same way as phthalimide or its potassium salt, but neither strong acid or base nor hydrazine is needed to cleave off the protecting group(s). Besides, the approaches described above to prepare imidodicarbonates and acylcarbamates are in principle rather flexible and should, if necessary, allow additional, selectively protected compounds to be made in the same way. Thus, the imide concept as such has withstood the ravages of time since its introduction a century ago. In parallel, much work aimed at the direct alkylation of amides has recently been performed, and in many cases it is now possible to obtain specific, relatively simple amides from which the corresponding amines can be regenerated. Many acyl groups used in this context require, however, cleavage conditions which occasionally cannot be tolerated, and the application of carbamates would probably be a better alternative in such cases.

psychokitty

It would appear that the potassium salt of saccharin could very possibly substitute fully for the potassium salt of phthalimide in the Gabriel synthesis of amines.

Anybee think that he/she can obtain a copy of the articles or abstracts listed at the bottom of this page/post? Hopefully they're printed in English.

Acc. Chem. Res., Vol. 24, No. 10, 2991

Taken from page 288:

Saccharin.

Sugasawa and Abe have introduced saccharin (1 1) as a replacement for phthalimide in the synthesis of amines by "the saccharin method" (ref 59) particularly to obtain secondary amines. The potassium salt is first monoalkylated, whereupon the imide ring is opened by alkaline hydrolysis to give an N-substituted sulfonamide. After acidification, the product is alkylated a second time. In this step actually 2 equivalents of the reagent are consumed, since the carboxylic group in the 2-position also reacts, and this ester is saponified. To isolate the secondary amine, heating with strong acid is required, normally giving products in good yields. The ring opening, second alkylation, and saponification can be performed consecutively without isolation of intermediates. The authors stress that the final hydrolysis takes place much more easily than in ordinary sulfonamides. The saccharin method has later been used by Abe for the synthesis also of diamines (ref 60), amino alcohols (ref 60), and less accessible secondary amines (refs 61 & 62). The mechanism of the reaction has also been discussed (ref 63).

The yield from the sodium saccharin example seems to be higher than that of the one using potassium phthalimide; furthermore, the reaction proceeds much quicker with the apparent need of a lower reaction temperature. I wonder why?

psychokitty

Syntheses of 3-methylamino-a-phenyl­propane and y-methylamino-a-phenylbutane.

Actually, "3-methylamino-a-phenylpropane" is listed as "B-methylamino-a-phenylpropane" in the abstract. Lugh: What makes you think that the "B" = "3"?

Ibid. 164-7. -PhCH2CHMeOH

Notice the middle carbon atom with one hydrogen atom attached. Carbon has the ability to create four bonds. No more. The carbon atom bonded directly to the phenyl group is also bonded to two hydrogen atoms and to the second carbon atom, which for the second carbon atom also represents one bond. The second carbon atom is bonded to one hydrogen atom, and also to the two carbon atoms--the first and third, to be exact--located on either side of it. THE SECOND CARBON ATOM IS THE ONLY ONE IN THE PROPANE SIDE CHAIN THAT CANNOT ACCOUNT FOR ONE OF ITS BONDS. Furthermore, the "OH" group cannot belong to the "Me" group (methyl group) as the Me group already has three hydrogen atoms along with the second carbon atom accounting for its four available bonds.

This part was typical of the advanced Gabriel synthesis using DMF as the solvent. Apparantly, the DMF helps to increase the reaction rate (probably via an SN2 reaction) and lower the reaction temperature, thus minimizing the formation of byproducts. Also, in the abstract, the saccharin intermediate is written as "N-(B-phenylisopropyl)saccharin" which seems very similar to B-phenylisopropylamine. Furthermore, why use "phenylisopropyl" prefix if not to indicate that the saccharin molecule is attached to the second central carbon atom on the propane side chain?

Apparently, aqueous NaOH hydrolysis of the alkylated saccharin intermediate allows for the cleavage of part of the saccharin molecule, protecting one side of the nitrogen atom, while leaving the other side available for further alkylation.

This part describes the hydrolysis of the final alkylated saccharin artifact to yield the desired monomethylated alkylated secondary amine; namely, B-methylamino-a-phenylpropane, better known as methamphetamine(?).

made alk. and the product steam distd. in dil. HC1 to obtain 1.2 g. (30% from XXIII) MeNHCHMeCH2Ph.HCI,

This part is definitely confusing because the way the atoms are all arranged, I really can't make heads or tails of the molecule's structure.

leaves, m. 131-3°; picrate, needles, m. 122°.

This is where I pretty much determined that the product of this reaction--of "the saccharin method"--was actually methamphetamine.

The m.p. of d,l-methamphetamine-HCl is about 132-135 C.; the m.p. reported for the product above is 131-133 C. Almost right on the money. As for methamphetamine picrate, it's listed as 128 C. Only six degrees away from what is reported above, 122 C.

Final comments.

It would appear that in order to resolve this mystery, the actual Journal of the Pharmaceutical Society of Japan articles will have to be fetched by someone who has access to them. No doubt, somewhere within the pages of the original articles--likely along with valuable and useful references to past Gabriel syntheses--will be found diagrams of the molecules in question that will help determine once and for all whether or not "B-methylamino-a-phenylpropane" is indeed synonymous with "methamphetamine".